2. Academic Validation
  3. Targeting P2RX1 alleviates renal ischemia/reperfusion injury by preserving mitochondrial dynamics

Targeting P2RX1 alleviates renal ischemia/reperfusion injury by preserving mitochondrial dynamics

  • Pharmacol Res. 2021 Aug;170:105712. doi: 10.1016/j.phrs.2021.105712.
Shaoyong Zhuang 1,  Shengqiang Xia 1,  Peiqi Huang 2,  Jiajin Wu 1,  Junwen Qu 1,  Ruoyang Chen 1,  Nan Sun 1,  Dawei Li 1,  Haoyu Wu 1,  Ming Zhang 3,  Jianjun Zhang 4,  Xiaodong Yuan 5,  Xu Wang 6
Affiliations

Affiliations

  • 1 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 2 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 3 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: drmingzhang@126.com.
  • 4 Department of Liver Surgery, Liver Transplantation Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: zhangjianjun0221@126.com.
  • 5 Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: sduyuanxd@126.com.
  • 6 Department of Liver Surgery, Liver Transplantation Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: wangxu@ujs.edu.cn.
PMID: 34091010 DOI: 10.1016/j.phrs.2021.105712
Abstract

Renal ischemia/reperfusion injury (IRI) is the major cause of acute kidney injury. However, mechanisms underlying the sudden loss in kidney function and tissue injury remain to be fully elucidated. Here, we performed RNA Sequencing to systematically compare the transcriptome differences between IR injured kidneys and sham kidneys. We observed that mitochondrial dynamics was destructed in renal IRI. Expression of mitochondrial fusion-associated genes was reduced, whereas expression of mitochondrial fission-related genes was increased in renal IRI, and these findings were further confirmed by mitochondrial morphological observations. By screening 19 purinergic receptors, we noticed that P2RX1 expression was markedly upregulated in renal IRI. RNA Sequencing and mitochondrial morphological observations revealed that mitochondrial dynamics was preserved in P2RX1 genetic knockout (P2rx1-/-) mice. Neutrophil extracellular traps (NETs) were reported to be essential for tissue injury in renal IRI, but the detailed mechanism remained unclear. In the present study, we found that P2RX1 favored the formation of neutrophil extracellular traps (NETs) in IRI, and NETs was essential for the impairment of mitochondrial dynamics. Mechanistically, P2RX1-involved metabolic interaction between platelets and neutrophils supported NETs formation. Activation of P2RX1 promoted platelets ATP release, which subsequently contributed to neutrophil glycolytic metabolism and NETs generation.

Keywords

Mitochondrial dynamics; Neutrophil; P2RX1; Renal ischemia/reperfusion.

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